Evolutionary rewiring of the dynamic network underpinning allosteric epistasis in NS1 of the influenza A virus

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(8)

Published: Feb. 20, 2025

Viral proteins frequently mutate to evade host innate immune responses, yet the impact of these mutations on molecular energy landscape remains unclear. Epistasis, intramolecular communications between mutations, often renders combined mutational effects unpredictable. Nonstructural protein 1 (NS1) is a major virulence factor influenza A virus (IAV) that activates PI3K by binding its p85β subunit. Here, we present deep analysis evolutionary in NS1 emerged 1918 pandemic IAV strain and descendant PR8 strain. Our reveals how rewired interresidue communications, which underlie long-range allosteric epistatic networks NS1. findings show binds with approximately 10-fold greater affinity than due effects, are further tuned epistasis. NMR chemical shift perturbation methyl-axis order parameter analyses revealed induced structural dynamic changes NS1, relative enhancing p85β. Complementary dynamics simulations graph theory-based network for conformational submicrosecond timescales uncover rewire network, underlies Significantly, find residues high betweenness centrality play crucial role communities highly conserved across evolution. These advance our mechanistic understanding distant provide insight into their evolution

Language: Английский

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Allostery

Quarterly Reviews of Biophysics, Journal Year: 2025, Volume and Issue: 58

Published: Jan. 1, 2025

Abstract Allostery describes the ability of biological macromolecules to transmit signals spatially through molecule from an allosteric site – a that is distinct orthosteric binding sites primary, endogenous ligands functional or active site. This review starts with historical overview and description classical example allostery hemoglobin other well-known examples (aspartate transcarbamoylase, Lac repressor, kinases, G-protein-coupled receptors, adenosine triphosphate synthase, chaperonin). We then discuss fringe allostery, including intrinsically disordered proteins inter-enzyme influence dynamics, entropy, conformational ensembles landscapes on mechanisms, capture essence field. Thereafter, we give over central methods for investigating molecular covering experimental techniques as well simulations artificial intelligence (AI)-based methods. conclude allostery-based drug discovery, its challenges opportunities: recent advent AI-based methods, compounds are set revolutionize discovery medical treatments.

Language: Английский

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The Evolving Landscape of Protein Allostery: From Computational and Experimental Perspectives

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169060 - 169060

Published: March 1, 2025

Language: Английский

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Adaptive Workflows of Machine Learning Illuminate the Sequential Operation Mechanism of the TAK1′s Allosteric Network

Biochemistry, Journal Year: 2024, Volume and Issue: 63(11), P. 1474 - 1492

Published: May 14, 2024

Allostery is a fundamental mechanism driving biomolecular processes that holds significant therapeutic concern. Our study rigorously investigates how two distinct machine-learning algorithms uniquely classify already close-to-active DFG-in states of TAK1, differing just by the presence or absence its allosteric activator TAB1, from an ensemble mixture conformations (obtained 2.4 μs molecular dynamics (MD) simulations). The novelty, however, lies in understanding deeper algorithmic potentials to systematically derive diverse set differential residue connectivity features reconstruct essential mechanistic architecture for TAK1-TAB1 allostery such biochemical scenario. While recursive, random forest-based workflow displays potential conducting discretized, hierarchical derivation features, multilayer perceptron-based approach gains considerable efficacy revealing fluid connected patterns when hybridized with mutual information scoring. Interestingly, both pipelines benchmark similar directions functional conformational changes TAK1's activation. findings significantly advance depth highlighting crucial activation signatures along directed C-lobe → loop ATP pocket channel flow, including (1) αF-αE biterminal alignments and (2) "catalytic" drift toward kinase active site. Besides, some novel hotspots (K253, Y206, N189, etc.) are further recognized as TAB1 sensors, transducers, responders, E70 mutation site, precisely mapping important structural segments sequential execution. Hence, our work demonstrates navigate through greater depths dimensions dynamic machineries leveraging standard ML methods suitable streamlined workflows adaptive specific system objectives.

Language: Английский

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Insights into Ligand-Mediated Activation of an Oligomeric Ring-Shaped Gene-Regulatory Protein from Solution- and Solid-State NMR

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 14, 2024

Abstract The 91 kDa oligomeric ring-shaped ligand binding protein TRAP ( trp RNA attenuation protein) regulates the expression of a series genes involved in tryptophan (Trp) biosynthesis bacilli. When cellular Trp levels rise, free amino acid binds to sites buried interfaces between each 11 (or 12, depending on species) protomers ring. Crystal structures Trp-bound show ligands are sequestered from solvent by pair loops adjacent that bury bound via polar contacts several threonine residues. Binding occurs cooperatively, such successive events occur with higher apparent affinity but structural basis for this cooperativity is poorly understood. We used solution methyl-TROSY NMR relaxation experiments focused and isoleucine sidechains, as well magic angle spinning solid-state 13 C- C 15 N- chemical shift correlation spectra uniformly labeled samples recorded at 800 1200 MHz, characterize structure dynamics protein. Methyl dispersion ligand-free apo revealed concerted exchange µs-ms time scale, consistent transient sampling conformations could allow binding. Cross-correlated widespread disorder fast timescales. Chemical shifts methyl-bearing side chains apo- subtle changes distribution sampled sidechain rotameric states. These observations reveal pathway mechanism induced conformational generate homotropic Trp-Trp cooperativity.

Language: Английский

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Evolutionary rewiring of the dynamic network underpinning allosteric epistasis in NS1 of influenza A virus

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 26, 2024

Abstract Viral proteins frequently mutate to evade or antagonize host innate immune responses, yet the impact of these mutations on molecular energy landscape remains unclear. Epistasis, intramolecular communications between mutations, often renders combined mutational effects unpredictable. Nonstructural protein 1 (NS1) is a major virulence factor influenza A virus (IAV) that activates PI3K by binding its p85β subunit. Here, we present deep analysis for evolutionary in NS1 emerged 1918 pandemic IAV strain and descendant PR8 strain. Our reveal how rewired inter-residue which underlies long-range allosteric epistatic networks NS1. findings show binds with approximately 10-fold greater affinity than due effects. Notably, also exhibited NMR chemical shift perturbation methyl-axis order parameter analyses revealed induced structural dynamic changes NS1, enhancing p85β. Complementary MD simulations graph-based network uncover rewire residue interaction networks, epistasis p85β-binding affinity. Significantly, find conformational dynamics residues high betweenness centrality play crucial role communities are highly conserved across evolution. These advance our mechanistic understanding distant provides insight into their evolution

Language: Английский

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Insights into Ligand-Mediated Activation of an Oligomeric Ring-Shaped Gene-Regulatory Protein from Solution- and Solid-State NMR

Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: unknown, P. 168792 - 168792

Published: Sept. 1, 2024

Language: Английский

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Targeting SHP2 Cryptic Allosteric Sites for Effective Cancer Therapy

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(11), P. 6201 - 6201

Published: June 4, 2024

SHP2, a pivotal component downstream of both receptor and non-receptor tyrosine kinases, has been underscored in the progression various human cancers neurodevelopmental disorders. Allosteric inhibitors have proposed to regulate its autoinhibition. However, oncogenic mutations, such as E76K, convert SHP2 into open state, wherein catalytic cleft becomes fully exposed ligands. This study elucidates dynamic properties structures across different states, with focus on effects mutation two known binding sites allosteric inhibitors. Through extensive modeling simulations, we further identified an alternative pocket solution structures. Additional analysis provides insights dynamics stability potential site. In addition, multi-tier screening was deployed identify binders targeting Our efforts new site contribute community-wide initiatives developing therapies using multiple target distinct pockets hope potentially inhibiting or slowing tumor growth associated SHP2.

Language: Английский

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Insights into the Allosteric Regulation of Human Hsp90 Revealed by NMR Spectroscopy

Biomolecules, Journal Year: 2024, Volume and Issue: 15(1), P. 37 - 37

Published: Dec. 30, 2024

Human heat shock protein 90 (Hsp90) is one of the most important chaperones that play a role in late stages folding. Errors process chaperone cycle can lead to diseases such as cancer and neurodegenerative diseases. Therefore, activity Hsp90 must be carefully regulated. One possibilities allosteric regulation by its natural modulators-nucleotides, co-chaperones client proteins-and synthetic small-molecule modulators, those targeting middle domain or C-terminal (CTD) Hsp90. Since no experimentally determined structure modulator bound CTD human has yet been obtained, challenge for structure-based design modulators remains. Solution nuclear magnetic resonance (NMR) spectroscopy could utilized overcome these problems. The main aim this review article discuss how solution NMR techniques, especially protein-based, advanced isotope labeling proteins have used investigate cytosolic isoforms with modulators. This provides basis planning future experiments, gaining insights into sites mechanisms regulation.

Language: Английский

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